A Restrictive Benzodiazepine Strategy During Cardiac Surgery Does Not Reduce Post-Operative Delirium

By Leah Kosyakovsky on

Key Points:

  • Benzodiazepine use contributes to delirium before and after cardiac surgery, but intra-operative benzodiazepine use has not been well-studied.
  • In B-Free, a restrictive intraoperative benzodiazepine strategy was compared with a liberal benzodiazepine strategy in the reduction of post-operative delirium.
  • In the primary intention-to-treat analysis, the restrictive benzodiazepine strategy did not result in a significant reduction in post-operative delirium. However, this endpoint was significantly reduced in the restrictive arm using either an on-policy analysis approach or after excluding patients receiving pre-operative benzodiazepines. 

Benzodiazepine use before and after cardiac surgery has previously been associated with delirium, but there is a dearth of evidence regarding intra-operative benzodiazepine use. A restrictive intra-operative benzodiazepine strategy could potentially contribute to reduced post-operative delirium and subsequent reduced length of stay and in-hospital morbidity and mortality. In a breaking presentation at the 2024 ACC conference today, Dr. Jessica Spence (McMaster University, Hamilton) and her team presented their study: “B-Free: Benzodiazepine-free Cardiac Anesthesia for Reduction of Postoperative Delirium.”

The B-Free study was a multicenter, cluster-randomized, crossover trial examining whether an institutional policy of benzodiazepine-free anesthesia during cardiac surgery reduced delirium 72 hours after surgery. The two study intervention arms included a) restricted benzodiazepine policy, with no routine use of benzodiazepines, and b) liberal benzodiazepine policy with ≥ 0.03 mg/kg midazolam. The primary outcome was delirium up to 72 hours after cardiac surgery, as assessed by bedside nurses. Key secondary outcomes included  a safety outcome (“intraoperative awareness”) and a post-hoc outcome (number of positive delirium assessments). The primary outcome was examined using an intention-to-treat approach with a logistic mixed model and was adjusted for age, sex, emergency surgery, and history of alcohol and benzodiazepine use.

A total of 19,768 patients were 1:1 randomized across 20 hospitals in North America to either a restricted (n=9,827) or liberal (n=9,941) policy. There was 92% adherence to the assigned policy. The mean age was 65 with 27% women, and 7% of participants had a history of home benzodiazepine use. The majority of included surgeries were either CABG (49%), isolated valve (17%), or other (34%). The mean time on cardiopulmonary bypass was 116±58 minutes. The restricted benzodiazepine policy did not result in a significant reduction in the primary endpoint by 72 hours (14% vs 14.9%, HR 0.92, 95% CI [0.84-1.01]; p=0.07). Additionally, there were no differences in the safety endpoint of intraoperative awareness (0% vs 0%). However, in post-hoc analyses, there was a lower number of positive delirium assessments over 72 hours in the restrictive group (HR 0.87, 95% CI [0.78-0.98]; p=0.02). After excluding individuals who received benzodiazepines within 24 hours of surgery, the primary endpoint was significantly reduced in the restrictive group (HR 0.88, 95% CI [0.81-0.97]; p=0.01). When using an on-policy analysis rather than intention-to-treat, the primary endpoint was similarly reduced in the restrictive arm (HR 0.90, 95% CI [0.82-0.99]; p=0.02).

When discussing the clinical implications of the study at the ACC conference, Dr. Spence stated: “By intention-to-treat, restricted benzodiazepine policy did not reduce postoperative delirium…with no evidence of adverse events…but considering the on-policy analysis showing 10% reduction in delirium…restricting benzodiazepines during cardiac surgery should be considered.”